Chemoenzymatic Synthesis of Antiviral Carbocyclic Nucleosides:  Asymmetric Hydrolysis of meso-3,5-Bis(acetoxymethyl)cyclopentenes Using Rhizopus delemar Lipase

Tanaka, Masakazu; Norimine, Yoshihiko; Fujita, Toshiaki; Shimizu, Hiroshi; Saito, Kiyoshi

doi:10.1021/jo9608230

Cited by 43 publications

(10 citation statements)

References 22 publications

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“…Intermediate A was developed from bis(acetate) 4 3. Protection with TBS, deacetylation, and nosylation of the primary alcohol afforded 5 (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Total Syntheses of Hexacyclinol, 5‐epi‐Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif

Clair

2006

Angew Chem Int Ed

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Hexacyclinol (1) was isolated by Gräfe and co-workers from the basidiospores collected from Panus rudis growing on dead betula woods in Siberia. [1] In 1999, our exploration into German fungal cultures provided a strain of P. rudis 99-329 that was not only capable of the biosynthesis of 1 but also provided trace amounts of epi-5-hexacyclinol (2) and desoxohexacyclinol (3). [2] Further study indicated that the retrocycloaddition of 1 and 2 released oxygen to afford a mixture of trienes 3 (Scheme 1). Subsequent [2+2+2] cycloaddition of 3 with singlet oxygen returned a mixture of 1 and 2. As this process could be cycled, it offered a key handle in expediting the synthesis of this family of terpenes.The synthesis of 1 and 2 through 3 simplifies the complexity of the hexacyclinol ring system by removal of the D/E rings (Scheme 1). On the basis of this argument, a campaign to 3 was launched using the synthetic plan outlined in Scheme 2. The plan began with an intact A ring as shown in intermediate A. The first stage of this project sought a rapid appendage of C7 and C17 onto A followed by the installation of the lower half of the B ring as given by the conversion of D into E. From E, a series of three sequences (E!F, F!G, and G!I, Scheme 2) were used to stitch the molecule together, beginning with the insertion of C15-C16, followed by creation of the C17-C18 bond, and ending with installation of the C14-C15 epoxide.Intermediate A was developed from bisA C H T U N G T R E N N U N G (acetate) 4.[3] Protection with TBS, deacetylation, and nosylation of the primary alcohol afforded 5 (Scheme 3). Under these conditions, nosylate 5 was obtained along with a bisA C H T U N G T R E N N U N G (nosylate) derivative (3-5 % yield), which was removed after treatment of the mixture with sodium cyanide in DMSO to convert 5 into 6. This sequence was conducted on a multigram scale to provide 6 after a single chromatographic purification step. The synthesis of 6 completed the installation of C7 as indicated by the conversion of A into B (Scheme 2).The next stage in this synthesis involved the installation of C17, as given by the conversion of B into C (Scheme 2). This operation was accomplished through the conversion of 6 into bromoacetal 7 by reaction with 1,2-dibromoethylmethyl ether (Scheme 3). [4] Treatment of crude 7 with NaHMDS at À78 8C followed by warming to room temperature resulted in 3:2 mixture of 8 a/8 b. Fortunately, protonation of the enolate of 8 a/8 b with triphenylacetic acid afforded a mixture favoring the desired nitrile 8 a by 11:1. To increase the material throughput to 8 a, the cyclization and isomerization steps were conducted in a one-pot operation.With intermediate C in hand, the next step required correction of the stereochemistry at C13. As provided by 4, this center required inversion as illustrated by the conversion into D (Scheme 2). The process began by convertion of the nitrile of 8 a to dithiane 13 (Scheme 3). Slow addition of DIBAL-H at À20 8C to 8 a at À78 8C in toluene afforded 9 in high yield. The ...

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“…Intermediate A was developed from bis(acetate) 4 3. Protection with TBS, deacetylation, and nosylation of the primary alcohol afforded 5 (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Total Syntheses of Hexacyclinol, 5‐epi‐Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif

Clair

2006

Angew Chem Int Ed

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“…IR spectra were recorded as neat liquids or KBr pellets and absorptions are reported in cm −1 . NMR spectra were measured on a Bruker 400 MHz Avance instrument at 400 MHz for 1 H and 100 MHz for 13 C NMR, using tetramethylsilane as an internal reference and CDCl 3 or d 6 -DMSO as a solvent. Chemical shift values for protons are reported in parts per million ( ppm, δ scale) downfield from tetramethylsilane and are referenced to residual proton of CDCl 3 (δ 7.26) or residual protons of d 6 -DMSO (δ 2.50).…”

Section: Methodsmentioning

confidence: 99%

Enantioselective synthesis of the carbocyclic nucleoside (−)-abacavir

Boyle

Edlin²,

et al. 2012

Org. Biomol. Chem.

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“…The recent discovery of branched carbocyclic nucleosides such as 6Ј(α)-hydroxymethyl carbovir 2 [9] and 6Ј(α)-methyl-carbathymidine 3 [10] as potential antiviral and antitumor agents has encouraged the search for novel nucleosides in this class of compounds (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiviral Evaluation of Novel 6′(α)‐Methyl‐Branched Carbovir Analogues

Kim

Hong

2005

Archiv der Pharmazie

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A new stereoselective synthesis of 6'-branched Carbovir analogues was accomplished in this study. The introduction of a methyl group in the requisite 6'(alpha)-position was carried out using an ester enolate alkylation (LHMDS, CH3I). The desired cyclopentenol 7 was synthesized via a Felkin-Anh-controlled Grignard addition and ring-closing metathesis using second-generation Grubbs' catalyst. The natural bases (adenine, cytosine) were efficiently coupled using a Pd(0) catalyst. When the synthesized compounds were examined for their activity against several viruses such as the HIV-1, HSV-1, HSV-2, and HCMV, the adenine analogue 12 exhibited moderate antiviral activity against the HCMV.

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Chemoenzymatic Synthesis of Antiviral Carbocyclic Nucleosides: Asymmetric Hydrolysis of meso-3,5-Bis(acetoxymethyl)cyclopentenes Using Rhizopus delemar Lipase

Cited by 43 publications

References 22 publications

Total Syntheses of Hexacyclinol, 5‐epi‐Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif

Total Syntheses of Hexacyclinol, 5‐epi‐Hexacyclinol, and Desoxohexacyclinol Unveil an Antimalarial Prodrug Motif

Enantioselective synthesis of the carbocyclic nucleoside (−)-abacavir

Synthesis and Antiviral Evaluation of Novel 6′(α)‐Methyl‐Branched Carbovir Analogues

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